(S)-Pregabalin, (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid, a compound having the chemical structure,
is also known as γ-amino butyric acid or (S)-3-isobutyl GABA. (S)-Pregabalin has been found to activate GAD (L-glutamic acid decarboxylase). (S)-Pregabalin has a dose dependent protective effect on-seizure, and is a CNS-active compound. (S)-Pregabalin is useful in anticonvulsant therapy, due to its activation of GAD, promoting the production of GABA, one of the brain's major inhibitory neurotransmitters, which is released at 30 percent of the brains synapses. (S)-Pregabalin has analgesic, anticonvulsant, and anxiolytic activity.
In the synthesis disclosed in U.S. Pat. No. 5,616,793, (S)-Pregabalin is obtained after optical resolution of the (±)-3-(carbamoylmethyl)-5-methylhexanoic acid racemate (referred to as CMH-racemate), which is accomplished by reaction of the CMH-racemate with chiral phenylethylamine in a solvent mixture of CHCl3 and ethanol to obtain the desired R-enantiomer of CMH according to the following scheme:
However, according to Chemical Development of CI-1008, An Enantiomerically Pure Anticonvulsant, ORGANIC PROCESS RESEARCH & DEVELOPMENT, 1997, 1, 26-38, this synthetic method was avoided because it requires the use of chloroform.
In the synthesis disclosed in DRUGS OF THE FUTURE, 24 (8), 862-870 (1999), CMH-racemate is also resolved with (R)-1-phenylethylamine, yielding the (R)-phenylethylamine salt of (R)—CMH. Combining the salt with an acid liberates the R enantiomer. Finally, Hoffmann degradation with Br2/NaOH provides (S)-Pregabalin. However, the optical resolution is done using a mixture of EtOH and chloroform, and therefore is problematic.
Optical resolution of a racemic mixture, particularly of carboxylic acids and amines, is performed via a diastereomeric salt. An example of this method is depicted in the following scheme,
The salt is formed by reacting the racemic mixture with a chiral resolving reagent. Then, a selective crystallization of only one of the diastereomers is done to isolate the desired diastereomer salt, while the undesired remains in the solution. The crystalline salt is then isolated and the chiral resolving reagent is removed to give the desired enantiomer. Accordingly, CMH which has a carboxylic acid function can be reacted with an appropriate chiral amine to obtain the salt of the desirable enantiomer (R-enantiomer), which is then isolated followed by removing the chiral amine to give (R)—CMH.

Thus, there is a need for an optical resolution process that overcomes the limitations of the above resolution procedures.